Acta Diabetologica (2021) 58:1131–1138 https://doi.org/10.1007/s00592-021-01727-5

REVIEW ARTICLE

The relationship between , short‑chain fatty acids and type 2 diabetes mellitus: the possible role of dietary fbre

Dominic Salamone1 · Angela Albarosa Rivellese1,2 · Claudia Vetrani1,2

Received: 19 January 2021 / Accepted: 19 April 2021 / Published online: 10 May 2021 © The Author(s) 2021

Abstract Gut microbiota and its metabolites have been shown to infuence multiple physiological mechanisms related to human health. Among microbial metabolites, short-chain fatty acids (SCFA) are modulators of diferent metabolic pathways. On the other hand, several studies suggested that diet might infuence gut microbiota composition and activity thus modulating the risk of metabolic disease, i.e. , insulin resistance and type 2 diabetes. Among dietary component, dietary fbre may play a pivotal role by virtue of its prebiotic efect on fbre-fermenting , that may increase SCFA production. The aim of this review was to summarize and discuss current knowledge on the impact of dietary fbre as modulator of the relationship between glucose metabolism and microbiota composition in humans. More specifcally, we analysed evidence from obser- vational studies and randomized nutritional intervention investigating the relationship between gut microbiota, short-chain fatty acids and glucose metabolism. The possible mechanisms behind this association were also discussed.

Keywords Gut microbiota · Short-chain fatty acids · Type 2 Diabetes · Insulin resistance · Glucose tolerance · Dietary fbre

Introduction composition, named “dysbiosis”, in prediabetic or T2D patients compared to healthy subjects [2, 3]. However, no The gut microbiota is a complex and dynamic ecosystem specifc microbial communities related to the onset of these that interacts with the host while maintaining a mutualistic diseases have been identifed so far. relationship with it. Indeed, it may infuence multiple physi- Nevertheless, more evidence is available on the microbial ological mechanisms related to human health, i.e. synthesis activities linked to the benefcial efect of the gut microbiota of micronutrients, defence against pathogens, regulation of against T2D [4]. The main mechanisms can be summarized glucose and lipid metabolism, and immune function [1]. as follows: (1) maintenance of the integrity of intestinal Therefore, it has been suggested that the modulation of barrier; (2) reduction in bacteria translocation and, conse- gut microbiota could be a reliable tool to prevent metabolic quently, systemic infammation (endotoxemia); (3) produc- and infammatory diseases. In particular, animal studies tion of short-chain fatty acids (SCFA) (acetate, propionate support a causal role between the composition of the gut and butyrate) which can infuence metabolic pathways [5]. microbiota and development of obesity, insulin resistance The frst two efects (maintenance of intestinal barrier and and type 2 diabetes (T2D). In addition, observational stud- reduction in endotoxemia) seem to be more closely linked to ies have confrmed the presence of altered gut microbiota the onset of diseases. Conversely, the production of SCFA could represent a tool to both prevent and modulate T2D [6, 7]. Managed by Massimo Federici . Against this background, several researches have been carried out to identify potential strategies to induce specifc * Angela Albarosa Rivellese [email protected] changes in the gut microbiota composition towards micro- bial species with high fermentative activity. 1 Department of Clinical Medicine and Surgery, University Gut microbiota composition is infuenced by internal and of Naples “Federico II”, 5 Sergio Pansini, 80131 Naples, external factors. Recently, it was shown that genetics plays Italy a marginal role in the defnition of microbiota composi- 2 Task Force On Microbiome Studies, University of Naples tion [8]. As for external factors, faecal transplantations and “Federico II”, Naples, Italy

Vol.:(0123456789)1 3 1132 Acta Diabetologica (2021) 58:1131–1138 antibiotics have dramatic but temporary efects on the host microbiota [9]. Conversely, dietary changes could be more efective to induce lasting changes in the composition of gut microbiota. Among dietary components, dietary fbres play a pivotal role. In fact, it is well known that fbres are the main substrate for bacterial metabolism. Furthermore, recent fndings demonstrated that habitual fbre intake can endorse a “virtuous cycle”, consisting in the overgrowth of fbre-fermenting microbial groups while inhibition of other species [10]. Within this context, the prebiotic efect of dietary fbres might be a feasible strategy to prevent T2D, through the modulation of metabolic response. However, to date, there is no conclusive evidence to support this thesis, likely due to the lack of studies focusing primarily on the relationship between the composition of the gut microbiota and meta- Fig. 1 bolic response. Flow diagram of literature search Therefore, in this review, we summarized current evi- dence from observational and intervention studies performed glucose tolerance, prediabetes and T2D. Greater abundance in humans investigating the relationship between the com- of butyrate-producing bacteria was observed in individuals position of the gut microbiota, concentration of SCFA and with normal glucose tolerance than the other two groups. glucose metabolism. Furthermore, the possible mechanisms In line with these results, metagenomic studies showed underlying this association were also discussed. signifcant diferences in the composition of the gut micro- biota of healthy patients compared to diabetic patients in two separate cohorts in China and Europe. In particular, Rose- Methods buria and Faecalibacterium prausnitzii were identifed as highly discriminating bacteria between normoglycaemic Literature searching for this review was conducted by individuals and those with T2D [13, 14]. In addition, in a searching PubMed database for observational studies and cohort of 900 healthy individuals, Senna et al. [15] observed randomized controlled clinical trials on humans adults pub- that the abundance of butyrate-producing bacteria is associ- lished in the English language, during the last 20 years. The ated with a better insulin response during an oral glucose terms “dietary fbre OR fbre OR fbre-rich diet”, “short- tolerance test, i.e. a proxy of improved β cell function. chain fatty acids OR butyrate OR acetate OR propionate”, Looking at how dietary habits may infuence the com- “microbiota OR microbiome OR bacteria”, “type 2 diabetes position of the gut microbiota, the study by De Filippo OR prediabetes OR glucose intolerance OR insulin resist- et al. [16] pointed out relevant diferences in the compo- ance OR insulin response”, combined with the Boolean sition of gut microbiota in children from Africa and Italy. operator “AND”, were employed for the research. Specifcally, African children had increased Bacteroides This review includes studies published in journals in (mainly Prevotella and Xylanibacter) and reduced Firmi- the highest impact factor quartile in the “Endocrinology cutes, whereas Italian children presented an inverse trend. and Metabolism” or “Nutrition and Dietetics” areas. We This fnding can be ascribed to diferent dietary habits in the excluded reviews, acute studies and those not specifcally two cohorts: the former used to a plant-based diet (minor related to each issue of interest. Overall, our search retrieved cereals like millet and sorghum, legumes and vegetables) a total of 18 studies suitable for our review, 10 observational than the latter consuming an animal-based diet rich in fat studies and 8 randomized controlled trials (Fig. 1). and protein. This hypothesis is supported by the presence of bacterial strains that hydrolyse fbres, in particular cellulose and xylans, inducing a greater production of faecal SCFA in Observational studies African children compared to Italian children. As for other dietary pattern, the relationship between Observational studies showed that the composition of the Mediterranean Diet (MD), characterized by a high-fbre gut microbiota is strictly related to the host metabolic state intake, and microbial fermentation was explored in diferent (Table 1). In particular, two large cohort studies [11, 12] studies. Many authors highlighted that the more adhesion to analysed the composition of microbiota into three groups MD, the greater increase of Bacteroides abundance, mainly of individuals with different glucose tolerance: normal Prevotella [17, 18], or Bifdobacteria [19] and Roseburia

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Table 1 Evidence from observational studies Reference Participants Main results

[11] 44 healthy individuals, BMI 23.4 kg/m2 ↑Butyrate-producing bacteria in healthy individuals 64 individuals with pre-diabetes, BMI 24.9 kg/m2 ↑ Bacteroides e costridii in patients with pre-T2D 13 individuals with T2D, BMI 26.5 kg/m2 [12] 206 healthy individuals, BMI 28.2 kg/m2 ↓Butyrate-producing Bacteria both in prediabetes and T2D 220 individuals with pre-diabetes, BMI 28.3 kg/m2 individuals 58 individuals with T2D, BMI 31.6 kg/m2 [13] 53 individuals with T2D, BMI 20–40 kg/m2 ↑Roseburia ↑Faecalibacterium prausnitzii in healthy individuals 49 individuals with pre-diabetes, BMI 20–40 kg/m2 ↓Roseburia ↓Faecalibacterium prausnitzii in individuals with 43 healthy individuals, BMI 20–40 kg/m2 T2D [14] 182 healthy individuals, BMI 18-40Kg/m2 ↑Roseburia ↑Faecalibacterium prausnitzii in healthy individuals 183 individuals with T2D, BMI 18-40Kg/m2 ↓Roseburia ↓Faecalibacterium prausnitzii in individuals with T2D [15] 952 healthy individuals selected on the basis of genome, Butyrate-producing Bacteria play a protective role against T2D metagenomic sequences and SCFA [16] 30 children (1–6 years): Plant-based diet (FFQ) 15 African ↑Prevotella↑Xylanibacter ↓Firmicutes 15 Italian Animal-based diet (FFQ) ↓Prevotella ↓Xylanibacter ↑Firmicutes [17] 27 healthy individuals, BMI 19–28 kg/m2 High MD adherence (FFQ) ↑Bifdobacteria ↑Bacteroidates ↓Firmicutes:Bacteroidates ↑Faecal SCFA ↑Faecal propionate High animal protein intake (FFQ) ↓Bacteroidates ↑Firmicutes:Bacteroidates [18] 31 healthy individuals: High MD adherence (FFQ) 10 healthy individuals with low adherence to MD ↑Faecal SCFA BMI 21.2–31,2 kg/m2 ↑Faecal propionate 21 healthy individuals with high adherence to MD ↑Faecal butyrate BMI 21.6–31 kg/m2 [19] 116 healthy individuals, BMI 25–30 kg/m2 High MD adherence (FFQ) ↑Bifdobacteria ↑Faecal SCFA [20] 51 vegetarian individuals, BMI 19.4–24.4 kg/m2 Vegetarian Diet, Vegan Diet and Omnivore high MD adherence 51 vegan individuals, BMI 19.1–23.5 kg/m2 ↑Prevotella 51 omnivore individuals, BMI 20.1–24.1 kg/m2 ↑Faecal propionate

BMI Body mass index; MD Mediterranean diet; FFQ Food frequency questionnaire, SCFA Short-chain fatty acids; T2D Type 2 Diabetes.

[20]. In addition, in all these studies individuals more com- (25.6 ± 1.1 g/1000 kcal) from wholegrains, legumes, fruits pliant with MD showed increased concentrations of faecal and vegetables. The results showed that plant-based diet butyrate or faecal propionate [17–20]. increased plant-polysaccharide metabolizing bacteria (Prevotella and Roseburia) with an higher concentration of faecal SCFA in particular butyrate, as compared to Intervention trials Western diet [21]. More recently, an 8-week Mediterranean diet, rich in Randomized nutritional trials focusing on dietary modula- fbre (fbre: 19.3 ± 3.1 g/1000 kcal), has shown to increase tion of microbial composition and activity were carried out Intestinimonas butyriciproducens and Akkermansia mucin- using high-fbre diets or fbre-rich foods (Table 2). iphila abundance, and postprandial plasma butyrate concen- As for high-fbre diets, a short-term randomized con- trations, with an improvement in postprandial glucose and trolled clinical trials (4 days) in a small group of healthy insulin sensitivity in individuals with high cardiometabolic individuals compared the prebiotic effect of a West- risk, compared to Control Diet (fbre: 8.1 ± 2.3 g/1000 kcal). ern diet (WD) –based on the consumption of animal Interestingly, butyrate concentrations directly correlated foods (meat, eggs and cheese)—with low fibre intake with postprandial insulin sensitivity, evaluated by OGIS (9.36 ± 2.1 g/1000 kcal) or a plant-based diet, rich in fbre [22].

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Table 2 Evidence from randomized clinical trials Reference Study design Participants Duration Intervention Observed efects

[21] Crossover 10 healthy individuals 4 days Plant-based Diet (fbre: Plant-based diet BMI 19–32 kg/m2 26 g/1000 kcal) ↑Prevotella ↑Roseburia vs ↑Faecal butyrate Western Diet (fbre: 9.3 g/ 1000 kcal) Western diet ↓Prevotella↑Bacteroides [22] Parallel 29 individuals with at 8 weeks Mediterranean Diet (fbre: Mediterranean diet compared to control least one MetS criterion 19.3 g/1000 kcal) diet BMI 25–35 kg/m2 vs ↑Intestinimonas butyriciproducens Control Diet (fbre: 8.1 g/ 1000 kcal) ↑Akkermansia muciniphila ↑Plasma butyric acid ↓Postprandial glucose ↓Postprandial insulin ↑OGIS [23] Parallel 43 individuals with T2D 12 weeks High-fbre Diet (fbre:37.1 g) High-fbre diet compared to control BMI 25–35 kg/m2 vs diet Control Diet (fbre:16.1 g) ↑Faecal butyrate ↓HbA1c ↓Fasting glucose [24] Parallel 20 individuals with MetS 1 year Mediterranean Diet Mediterranean diet BMI 30-40Kg/m2 (fbre: 12.9 ± 0.2 g/Kcal, mainly from ↑Roseburia ↓Prevotella vegetables) ↑ISI vs High-fbre diet High-fbre Diet ↓Roseburia ↑Prevotella (fbre: 14.1 ± 0.2 g/1000 kcal, mainly ↑ISI form wholegrains) [25] Crossover 19 individuals with MetS 4 weeks Diet enriched with Arabinoxylan and Healthy- diet enriched BMI 25,9–41 kg/m2 Resistant starch with arabinoxylan and resistant starch (fbre:64 g) compared to Western diet style vs ↑Bifdobacteria Western diet (fbre:17.6 g) ↑Faecal SCFA ↑Faecal Butyrate [26] Parallel 40 individuals with MetS 12 weeks Wholegrain diet (total fbre: 40 g; Wholegrain diet compared to refned BMI 25–35 kg/m2 fbre from cereal:28.9 g) cereal diet vs ↑Plasma propionate Refned cereal diet (total fbre: ↓Postprandial insulin 22.1 g; fbre from cereal 11.8 g) [27] Crossover 39 healthy individuals 3 days Barley kernel-based bread Barley kernel-based bread compared to BMI 18–28 kg/m2 (fbre:37.6 g) white wheat bread vs ↑Prevotella:Bacteroides White wheat bread (fbre:9.1 g) ↓Postprandial glucose [28] Crossover 39 healthy individuals 3 days Barley kernel-based bread Barley kernel-based bread compared to BMI 18–28 kg/m2 (fbre:37,6 g) white wheat bread vs ↑Plasma SCFA White wheat bread (fbre:9.1 g) ↓Glucose ↓Insulin

BMI Body mass index; HbA1c Glycated hemoglobin; ISI Insulin sensitivity index; MetS Metabolic syndrome; OGIS Oral glucose insulin sensi- tivity; SCFA Short-chain fatty acids.

Even in individuals with T2D, a 12-week high-fbre diet (fbre: 14.1 ± 0.2 g/1000 kcal mainly from wholegrains) (fbre: 37.1 ± 1.9 g) has shown to increase faecal butyrate increased Prevotella, while Mediterranean Diet (fibre: concentrations that associated with the reduction in fasting 12.9 ± 0.2 g/1000 kcal, mainly from vegetables and nuts) glucose and HbA1c concentrations [23]. enhanced Roseburia abundance. Meanwhile both diets In addition, another trial in a small group of indi- increased Faecalibacterium prausnitzii. Interestingly, an viduals with metabolic syndrome has demonstrated that improved insulin sensitivity was observed after both diets plant-based diets may selectively increase some bacte- [24]. rial species, depending on the type of fbres consumed. Among high-fbre foods, wholegrains have been exten- Indeed, in a long-term clinic trial (1 year), a high-fbre diet sively studied by virtue of their high fbre content. Indeed,

1 3 Acta Diabetologica (2021) 58:1131–1138 1135 it has been shown that cereal fbre (arabinoxylans and bran) Accumulating evidence supports local—meaning in is highly fermentable and may increase faecal short-chain —and systemic efect of SCFA that fatty acid concentrations after just 4 weeks [25]. might afect glucose metabolism (Fig. 2). Moreover, a 12-week wholegrain-based diet (cereal fbre: Studies in vitro and in vivo showed that SCFA are 28.9 ± 1.1 g/day) has shown to increase plasma propionate potent secretagogues for glucagon-like peptide‑1 (GLP- concentration compared to a refned-cereal-based diet used 1) and peptide YY (PYY) that increase satiety feeling as control (cereal fbre: 11.8 ± 0.4 g/day), and this increase through the gut–brain axis. As a consequence, they might correlated with an improved insulin postprandial response indirectly reduce appetite and consequent food intake, thus in individuals with Metabolic Syndrome [26]. preventing body weight gain, a well-known risk factor As for the effect of specific foods, two studies [27, T2D. Moreover, SCFA might regulate blood glucose con- 28] have showed that the consumption of barley kernel- centrations through a GLP-1-mediated increase in insulin based bread (fbre: 37.6 g/day) increased Prevotella while secretion [30]. reduced Bacteroides after only 3 days compared to wheat In the liver, SCFA has shown to decrease glycolysis and bread (fbre: 9.1 g/day) in healthy volunteers. This change gluconeogenesis, and to increase glycogen synthesis and was associated with the reduction in postprandial glucose fatty acids oxidation [30–34]. response [27, 28] which correlated with the increased total As for extra intestinal effects, SCFA have shown to serum SCFA concentration [28]. improve glucose uptake in skeletal muscle and adipose tis- In conclusion, although many studies have been per- sue by increasing the expression of GLUT4, through AMP formed in small groups and with a short duration, the results Kinase (AMPK) activity. In addition, in the skeletal muscle, from the main intervention trials (Table 2) indicate that high- SCFA reduce glycolysis with a consequent accumulation fbre diets and fbre-rich foods are able to improve glucose of glucose-6-phosphate and increase in glycogen synthesis metabolism and this improvement is associated with changes [31–37]. in gut microbiota and increased SCFA concentration. The possible efects of SCFA, in particular butyrate and propionate, in the modulation of glucose metabolism in humans, pushed to carry out intervention studies with propi- Possible mechanisms of action onate and butyrate supplementation. However, the evidence is not conclusive since the studies are few and have been Dietary fbre has shown to infuence glucose metabolism by performed in small groups of individuals. Nevertheless, they several mechanisms in healthy individuals and people with seem to indicate that: 1) an inulin-propionate supplementa- T2D, mainly driven by its functional properties (viscosity, tion (10 g/day) increases GLP-1 and PYY, and reduces food water solubility, and fermentation rate) [29]. New insights intake [38, 39] thus contributing to body weight regulation, into the capacity of dietary fbre to modulate microbial com- and 2) sodium butyrate supplementation (4 g/day) improves position and activity triggered more attention on microbial insulin sensitivity only in lean subjects and not in individuals metabolites, particularly SCFA. with metabolic syndrome [40].

Fig. 2 Main mechanisms of action of short-chain fatty acids on glucose metabolism. GLP-1 Glucagon-like peptide‑1, GLUT-4 Activated glucose transporter protein-4, PYY Peptide YY, SCFAs Short-chain fatty acids

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Conclusion improve microbiota composition and activity to prevent metabolic diseases. Based on the current evidence, gut microbiota might play a pivotal role in the regulation of glucose metabolism and, Funding therefore, may be associated with a reduction in type 2 Open access funding provided by Università degli Studi di Napoli Federico II within the CRUI-CARE Agreement. diabetes risk. As already mentioned in Introduction, this association may be mediated by several mechanisms (i.e. Declarations maintenance of the integrity of intestinal barrier, reduced endotoxemia, and production of microbial metabolites). Conflict of interest The authors declare that they have no confict of Some bacteria (i.e. Akkermansia muciniphila, Lactobacil- interest. lus and Bifdobacteria) may reduce intestinal permeability and infammation [5, 41]. As for microbial metabolites, Open Access This article is licensed under a Creative Commons Attri- short-chain fatty acids (SCFAs) have shown pleiotropic bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long efects in diferent sites that regulate glucose metabolism. as you give appropriate credit to the original author(s) and the source, SCFAs acids are produced by microbiota through the fer- provide a link to the Creative Commons licence, and indicate if changes mentation of dietary fbre. At the same time, a fbre-rich were made. The images or other third party material in this article are diet has shown a prebiotic efect towards SCFA-producing included in the article’s Creative Commons licence, unless indicated Roseburia, Faecalibacterium praus- otherwise in a credit line to the material. If material is not included in microbial species (i.e. the article’s Creative Commons licence and your intended use is not nitzii, Prevotella) [42, 43]. This evidence supports micro- permitted by statutory regulation or exceeds the permitted use, you will biota as key actor in the interplay between fbre intake need to obtain permission directly from the copyright holder. To view a and the prevention and management of metabolic diseases. copy of this licence, visit http://creat​ iveco​ mmons.​ org/​ licen​ ses/​ by/4.​ 0/​ . Therefore, the well-known efect of dietary fbres in pre- venting T2D [44] may be explained, at least in part, also throughout this mechanism. Unfortunately, no studies have References evaluated specifcally whether soluble and insoluble fbres may diferently afect microbiota. According to fbre used 1. 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